Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof

ABSTRACT

Compounds of formula (I) or pharmaceutically acceptable salts thereof: wherein R1, R2, R3, R4 and Z are as defined in the specification as well as salts and pharmaceutical compositions including the compounds are prepared. They are useful in therapy, in particular in the management of pain.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a US National Stage under 35 U.S.C §371 ofInternational Application No. PCT/GB2004/002430, filed on 09 Jun. 2004,which claims priority under 35 U.S.C. §119(a)-(d) to Swedish ApplicationNo. 0301701-9 filed on 10 Jun. 2003.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention is related to therapeutic compounds which are CB₁ receptorligands, pharmaceutical compositions containing these compounds,manufacturing processes thereof and uses thereof, and more particularlyto compounds that are CB₁ receptor agonists. More particularly, thepresent invention is related to compounds that may be effective intreating pain, cancer, multiple sclerosis, Parkinson's disease,Huntington's chorea, Alzheimer's disease, anxiety disorders,gastrointestinal disorders and cardiovascular disorders.

2. Discussion of Relevant Technology

Pain management has been an important field of study for many years. Ithas been well known that cannabinoid receptor (e.g., CB₁ receptor, CB₂receptor) ligands including agonists, antagonists and inverse agonistsproduce relief of pain in a variety of animal models by interacting withCB₁ and/or CB₂ receptors. Generally, CB₁ receptors are locatedpredominately in the central nervous system, whereas CB₂ receptors arelocated primarily in the periphery and are primarily restricted to thecells and tissues derived from the immune system.

While CB₁ receptor agonists, such as Δ⁹-tetrahydrocannabinol (Δ⁹-THC)and anadamide, are useful in anti-nociception models in animals, theytend to exert undesired CNS side-effects, e.g., psychoactive sideeffects, the abuse potential, drug dependence and tolerance, etc. Theseundesired side effects are known to be mediated by the CB₁ receptorslocated in CNS. There are lines of evidence, however, suggesting thatCB1 agonists acting at peripheral sites or with limited CNS exposure canmanage pain in humans or animals with much improved overall in vivoprofile.

Therefore, there is a need for new CB₁ receptor ligands such asagonists, antagonists or inverse agonists that are useful in managingpain or treating other related symptoms or diseases with reduced orminimal undesirable CNS side-effects.

DISCLOSURE OF THE INVENTION

The present invention provides CB₁ receptor ligands which are useful intreating pain and other related symptoms or diseases.

Definitions

Unless specified otherwise within this specification, the nomenclatureused in this specification generally follows the examples and rulesstated in Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F,and H, Pergamon Press, Oxford, 1979, which is incorporated by referencesherein for its exemplary chemical structure names and rules on namingchemical structures. Optionally, a name of a compound may be generatedusing a chemical naming program: ACD/ChemSketch, Version 5.09/September2001, Advanced Chemistry Development, Inc., Toronto, Canada

“CB₁/CB₂ receptors” means CB₁ and/or CB₂ receptors.

The term “C_(m-n)” or “C_(m-n) group” used alone or as a prefix, refersto any group having m to n carbon atoms, and having 0 to n multivalentheteroatoms selected from O, S, N and P, wherein m and n are 0 orpositive integers, and n>m. For example, “C₁₋₆” would refer to achemical group having 1 to 6 carbon atoms, and having 0 to 6 multivalentheteroatoms selected from O, S, N and P.

The term “hydrocarbon” used alone or as a suffix or prefix, refers toany structure comprising only carbon and hydrogen atoms up to 14 carbonatoms.

The term “hydrocarbon radical” or “hydrocarbyl” used alone or as asuffix or prefix, refers to any structure as a result of removing one ormore hydrogens from a hydrocarbon.

The term “alkyl” used alone or as a suffix or prefix, refers tomonovalent straight or branched chain hydrocarbon radicals comprising 1to about 12 carbon atoms. Unless otherwise specified, “alkyl” generalincludes both saturated alkyl and unsaturated alkyl.

The term “alkylene” used alone or as suffix or prefix, refers todivalent straight or branched chain hydrocarbon radicals comprising 1 toabout 12 carbon atoms, which serves to links two structures together.

The term “alkenyl” used alone or as suffix or prefix, refers to amonovalent straight or branched chain hydrocarbon radical having atleast one carbon-carbon double bond and comprising at least 2 up toabout 12 carbon atoms.

The term “alkynyl” used alone or as suffix or prefix, refers to amonovalent straight or branched chain hydrocarbon radical having atleast one carbon-carbon triple bond and comprising at least 2 up toabout 12 carbon atoms.

The term “cycloalkyl,” used alone or as suffix or prefix, refers to amonovalent ring-containing hydrocarbon radical comprising at least 3 upto about 12 carbon atoms.

The term “cycloalkenyl” used alone or as suffix or prefix, refers to amonovalent ring-containing hydrocarbon radical having at least onecarbon-carbon double bond and comprising at least 3 up to about 12carbon atoms.

The term “cycloalkynyl” used alone or as suffix or prefix, refers to amonovalent ring-containing hydrocarbon radical having at least onecarbon-carbon triple bond and comprising about 7 up to about 12 carbonatoms.

The term “aryl” used alone or as suffix or prefix, refers to amonovalent hydrocarbon radical having one or more polyunsaturated carbonrings having aromatic character, (e.g., 4n+2 delocalized electrons) andcomprising 5 up to about 14 carbon atoms, wherein the radical is locatedon a carbon of the aromatic ring.

The term “non-aromatic group” or “non-aromatic” used alone, as suffix oras prefix, refers to a chemical group or radical that does notcontaining a ring having aromatic character (e.g., 4n+2 delocalizedelectrons).

The term “arylene” used alone or as suffix or prefix, refers to adivalent hydrocarbon radical having one or more polyunsaturated carbonrings having aromatic character, (e.g., 4n+2 delocalized electrons) andcomprising 5 up to about 14 carbon atoms, which serves to links twostructures together.

The term “heterocycle” used alone or as a suffix or prefix, refers to aring-containing structure or molecule having one or more multivalentheteroatoms, independently selected from N, O, P and S, as a part of thering structure and including at least 3 and up to about 20 atoms in thering(s). Heterocycle may be saturated or unsaturated, containing one ormore double bonds, and heterocycle may contain more than one ring. Whena heterocycle contains more than one ring, the rings may be fused orunfused. Fused rings generally refer to at least two rings share twoatoms therebetween. Heterocycle may have aromatic character or may nothave aromatic character.

The term “heteroalkyl” used alone or as a suffix or prefix, refers to aradical formed as a result of replacing one or more carbon atom of analkyl with one or more heteroatoms selected from N, O, P and S.

The term “heteroaromatic” used alone or as a suffix or prefix, refers toa ring-containing structure or molecule having one or more multivalentheteroatoms, independently selected from N, O, P and S, as a part of thering structure and including at least 3 and up to about 20 atoms in thering(s), wherein the ring-containing structure or molecule has anaromatic character (e.g., 4n+2 delocalized electrons).

The term “heterocyclic group,” “heterocyclic moiety,” “heterocyclic,” or“heterocyclo” used alone or as a suffix or prefix, refers to a radicalderived from a heterocycle by removing one or more hydrogens therefrom.

The term “heterocyclyl” used alone or as a suffix or prefix, refers amonovalent radical derived from a heterocycle by removing one hydrogenfrom a carbon of a ring of the heterocycle.

The term “heterocyclylene” used alone or as a suffix or prefix, refersto a divalent radical derived from a heterocycle by removing twohydrogens therefrom, which serves to links two structures together.

The term “heteroaryl” used alone or as a suffix or prefix, refers to aheterocyclyl having aromatic character, wherein the radical of theheterocyclyl is located on a carbon of an aromatic ring of theheterocyclyl.

The term “heterocylcoalkyl” used alone or as a suffix or prefix, refersto a heterocyclyl that does not have aromatic character.

The term “heteroarylene” used alone or as a suffix or prefix, refers toa heterocyclylene having aromatic character.

The term “heterocycloalkylene” used alone or as a suffix or prefix,refers to a heterocyclylene that does not have aromatic character.

The term “six-membered” used as prefix refers to a group having a ringthat contains six ring atoms.

The term “five-membered” used as prefix refers to a group having a ringthat contains five ring atoms.

A five-membered ring heteroaryl is a heteroaryl with a ring having fivering atoms wherein 1, 2 or 3 ring atoms are independently selected fromN, O and S.

Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl,imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl,1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl,1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

A six-membered ring heteroaryl is a heteroaryl with a ring having sixring atoms wherein 1, 2 or 3 ring atoms are independently selected fromN, O and S.

Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl,pyrimidinyl, triazinyl and pyridazinyl.

The term “substituted” used as a prefix refers to a structure, moleculeor group, wherein one or more hydrogens are replaced with one or moreC₁₋₁₂hydrocarbon groups, or one or more chemical groups containing oneor more heteroatoms selected from N, O, S, F, Cl, Br, I, and P.Exemplary chemical groups containing one or more heteroatoms includeheterocyclyl, —NO₂, —OR, —Cl, —Br, —I, —F, —CF₃, —C(═O)R, —C(═O)OH,—NH₂, —SH, —NH, —NR₂, —SR, —SO₃H, —SO₂R, —S(═O)R, —CN, —OH, —C(═O)OR,—C(═O)NR₂, —NRC(═O)R, oxo (═O), imino (═NR), thio (═S), and oximino(═N—OR), wherein each “R” is a C₁₋₁₂hydrocarbyl. For example,substituted phenyl may refer to nitrophenyl, pyridylphenyl,methoxyphenyl, chlorophenyl, aminophenyl, etc., wherein the nitro,pyridyl, methoxy, chloro, and amino groups may replace any suitablehydrogen on the phenyl ring.

The term “substituted” used as a suffix of a first structure, moleculeor group, followed by one or more names of chemical groups refers to asecond structure, molecule or group, which is a result of replacing oneor more hydrogens of the first structure, molecule or group with the oneor more named chemical groups. For example, a “phenyl substituted bynitro” refers to nitrophenyl.

The term “optionally substituted” refers to both groups, structures, ormolecules that are substituted and those that are not substituted.

Heterocycle includes, for example, monocyclic heterocycles such as:aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine,pyrroline, imidazolidine, pyrazolidine, pyrazoline, dioxolane, sulfolane2,3-dihydrofuran, 2,5-dihydrofuran tetrahydrofuran, thiophane,piperidine, 1,2,3,6-tetrahydro-pyridine, piperazine, morpholine,thiomorpholine, pyran, thiopyran, 2,3-dihydropyran, tetrahydropyran,1,4-dihydropyridine, 1,4-dioxane, 1,3-dioxane, dioxane, homopiperidine,2,3,4,7-tetrahydro-1H-azepine homopiperazine, 1,3-dioxepane,4,7-dihydro-1,3-dioxepin, and hexamethylene oxide.

In addition, heterocycle includes aromatic heterocycles, for example,pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, furazan,pyrrole, imidazole, thiazole, oxazole, pyrazole, isothiazole, isoxazole,1,2,3-triazole, tetrazole, 1,2,3-thiadiazole, 1,2,3-oxadiazole,1,2,4-triazole, 1,2,4-thiadiazole, 1,2,4-oxadiazole, 1,3,4-triazole,1,3,4-thiadiazole, and 1,3,4-oxadiazole.

Additionally, heterocycle encompass polycyclic heterocycles, forexample, indole, indoline, isoindoline, quinoline, tetrahydroquinoline,isoquinoline, tetrahydroisoquinoline, 1,4-benzodioxan, coumarin,dihydrocoumarin, benzofuran, 2,3-dihydrobenzofuran, isobenzofuran,chromene, chroman, isochroman, xanthene, phenoxathiin, thianthrene,indolizine, isoindole, indazole, purine, phthalazine, naphthyridine,quinoxaline, quinazoline, cinnoline, pteridine, phenanthridine,perimidine, phenanthroline, phenazine, phenothiazine, phenoxazine,1,2-benzisoxazole, benzothiophene, benzoxazole, benzthiazole,benzimidazole, benztriazole, thioxanthine, carbazole, carboline,acridine, pyrolizidine, and quinolizidine.

In addition to the polycyclic heterocycles described above, heterocycleincludes polycyclic heterocycles wherein the ring fusion between two ormore rings includes more than one bond common to both rings and morethan two atoms common to both rings. Examples of such bridgedheterocycles include quinuclidine, diazabicyclo[2.2.1]heptane and7-oxabicyclo[2.2.1]heptane.

Heterocyclyl includes, for example, monocyclic heterocyclyls, such as:aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl,dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl,tetrahydrofuranyl, thiophanyl, piperidinyl,1,2,3,6-tetrahydro-pyridinyl, piperazinyl, morpholinyl, thiomorpholinyl,pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl,1,4-dihydropyridinyl, 1,4-dioxanyl, 1,3-dioxanyl, dioxanyl,homopiperidinyl, 2,3,4,7-tetrahydro-1H-azepinyl, homopiperazinyl,1,3-dioxepanyl, 4,7-dihydro-1,3-dioxepinyl, and hexamethylene oxidyl.

In addition, heterocyclyl includes aromatic heterocyclyls or heteroaryl,for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl,furyl, furazanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl,isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl, and 1,3,4 oxadiazolyl.

Additionally, heterocyclyl encompasses polycyclic heterocyclyls(including both aromatic or non-aromatic), for example, indolyl,indolinyl, isoindolinyl, quinolinyl, tetrahydroquinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, 1,4-benzodioxanyl, coumarinyl,dihydrocoumarinyl, benzofuranyl, 2,3-dihydrobenzofuranyl,isobenzofuranyl, chromenyl, chromanyl, isochromanyl, xanthenyl,phenoxathiinyl, thianthrenyl, indolizinyl, isoindolyl, indazolyl,purinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl,cinnolinyl, pteridinyl, phenanthridinyl, perimidinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxazinyl, 1,2-benzisoxazolyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benzimidazolyl,benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl,pyrolizidinyl, and quinolizidinyl.

In addition to the polycyclic heterocyclyls described above,heterocyclyl includes polycyclic heterocyclyls wherein the ring fusionbetween two or more rings includes more than one bond common to bothrings and more than two atoms common to both rings. Examples of suchbridged heterocycles include quinuclidinyl, diazabicyclo[2.2.1]heptyl;and 7-oxabicyclo[2.2.1]heptyl.

The term “alkoxy” used alone or as a suffix or prefix, refers toradicals of the general formula —O—R, wherein —R is selected from ahydrocarbon radical. Exemplary alkoxy includes methoxy, ethoxy, propoxy,isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy,and propargyloxy.

The term “aryloxy” used alone or as suffix or prefix, refers to radicalsof the general formula —O—Ar, wherein —Ar is an aryl.

The term “heteroaryloxy” used alone or as suffix or prefix, refers toradicals of the general formula —O—Ar′, wherein —Ar′ is a heteroaryl.

The term “amine” or “amino” used alone or as a suffix or prefix, refersto radicals of the general formula —NRR′, wherein R and R′ areindependently selected from hydrogen or a hydrocarbon radical.

“Acyl” used alone, as a prefix or suffix, means —C(═O)—R, wherein —R isan optionally substituted hydrocarbyl, hydrogen, amino or alkoxy. Acylgroups include, for example, acetyl, propionyl, benzoyl, phenyl acetyl,carboethoxy, and dimethylcarbamoyl.

Halogen includes fluorine, chlorine, bromine and iodine.

“Halogenated,” used as a prefix of a group, means one or more hydrogenson the group is replaced with one or more halogens.

“RT” or “rt” means room temperature.

A first ring group being “fused” with a second ring group means thefirst ring and the second ring share at least two atoms therebetween.

“Link,” “linked,” or “linking,” unless otherwise specified, meanscovalently linked or bonded.

When a first group, structure, or atom is “directly connected” to asecond group, structure or atom, at least one atom of the first group,structure or atom forms a chemical bond with at least one atom of thesecond group, structure or atom.

“Saturated carbon” means a carbon atom in a structure, molecule or groupwherein all the bonds connected to this carbon atom are single bond. Inother words, there is no double or triple bonds connected to this carbonatom and this carbon atom generally adopts an sp³ atomic orbitalhybridization.

“Unsaturated carbon” means a carbon atom in a structure, molecule orgroup wherein at least one bond connected to this carbon atom is not asingle bond. In other words, there is at least one double or triple bondconnected to this carbon atom and this carbon atom generally adopts a spor sp² atomic orbital hybridization.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The term “therapeutic” and “therapeutically” should becontrued accordingly. The term “therapy” within the context of thepresent invention further encompasses to administer an effective amountof a compound of the present invention, to mitigate either apre-existing disease state, acute or chronic, or a recurring condition.This definition also encompasses prophylactic therapies for preventionof recurring conditions and continued therapy for chronic disorders.

SUMMARY OF THE INVENTION

This invention encompasses compounds in accord with formula I:

wherein

Z is selected from O═ and S═;

R¹ is selected from C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,R⁵R⁶N—C₁₋₆alkyl, R⁵O—C₁₋₆alkyl, R⁵C(═O)N(—R⁶)—C₁₋₆-alkyl,R⁵R⁶NS(═O)₂—C₁₋₆alkyl, R⁵CS(═O)₂N(—R⁶)—C₁₋₆alkyl,R⁵R⁶NC(═O)N(—R⁷)—C₁₋₆alkyl, R⁵R⁶NS(═O)₂N(R⁷)—C₁₋₆alkyl,C₁₋₁₀aryl-C₁₋₆alkyl, C₆₋₁₀aryl -C(═O)—C₁₋₆alkyl,C₃₋₁₀cycloalkyl-C₁₋₆alkyl, C₄₋₈cycloalkenyl-C₁₋₆alkyl,C₃₋₆heterocyclyl-C₁₋₆alkyl, C₃₋₆heterocyclyl-C(═O)—C₁₋₆alkyl,C₁₋₁₀hydrocarbylamino, R⁵R⁶N—, R⁵O—, R⁵C(═O)N(—R⁶)—, R⁵R⁶NS(═O)₂—,R⁵CS(═O)₂N(—R⁶)—, R⁵R⁶NC(═O)N(—R⁷)—, R⁵R⁶NS(═O)₂N(R⁷)—, C₆₋₁₀aryl,C₆₋₁₀aryl-C(═O)—, C₃₋₁₀cycloalkyl, C₄₋₈cycloalkenyl, C₃₋₆heterocyclyland C₃₋₆heterocyclyl-C(═O)—; wherein said C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₆₋₁₀aryl-C₁₋₆alkyl, C₆₋₁₀aryl-C(═O)—C₁₋₆alkyl,C₃₋₁₀cycloalkyl-C₁₋₆alkyl, C₄₋₈cycloalkenyl-C₁₋₆alkyl,C₃₋₆heterocyclyl-C₁₋₆alkyl, C₃₋₆heterocyclyl-C(═O)—C₁₋₆alkyl,C₁₋₁₀hydrocarbylamino, C₆₋₁₀aryl, C₆₋₁₀aryl-C(═O), C₃₋₁₀cycloalkyl,C₄₋₈cycloalkenyl, C₃₋₆heterocyclyl or C₃₋₆heterocyclyl-C(═O)— used indefining R¹ is optionally substituted by one or more groups selectedfrom halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and—NR⁵R⁶;

R² is selected from the group consisting of C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₆alkyl,C₄₋₈-cycloalkenyl-C₁₋₆alkyl, C₃₋₆heterocycloalkyl-C₁₋₆alkyl,C₄₋₈cycloalkenyl, R⁵R⁶N—, C₃₋₅heteroaryl, C₆₋₁₀aryl and C₃₋₆heterocycloalkyl, wherein said C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₆alkyl, C₄₋₈-cycloalkenyl-C₁₋₆alkyl,C₃₋₆ heterocycloalkyl-C₁₋₆alkyl, C₄₋₈cycloalkenyl, C₃₋₅heteroaryl,C₆₋₁₀aryl or C₃₋₆heterocycloalkyl used in defining R² is optionallysubstituted by one or more groups selected from halogen, cyano, nitro,methoxy, ethoxy, methyl, ethyl, hydroxy, and —NR⁵R⁶;

wherein R⁵, R⁶ and R⁷ are independently selected from —H, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, and a divalent C₁₋₆group that together withanother divalent R⁵, R⁶ or R⁷ forms a portion of a ring; and

R³ is selected from R⁸, R⁸O—, and R⁸R⁹N—;

each of R⁴, R⁸ and R⁹ is independently selected from —H, C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₆alkyl,C₃₋₆heterocyclyl, C₆₋₁₀aryl, C₃₋₆heterocylcyl-C₁₋₆alkyl,C₆₋₁₀aryl-C₁₋₆alkyl, and a divalent C₁₋₆group that together with anotherdivalent group selected from R⁴, R⁸ and R⁹ forms a portion of a ring,wherein said C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀cycloalkyl,C₃₋₁₀cycloalkyl-C₁₋₆alkyl, C₃₋₆heterocyclyl, C₆₋₁₀aryl,C₃₋₆heterocylcyl-C₁₋₆alkyl, C₆₋₁₀aryl-C₁₋₆alkyl, or divalent C₁₋₆groupis optionally substituted by one or more groups selected from halogen,cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and —NR⁵R⁶.

The invention also encompasses stereoisomers, enantiomers,diastereomers, racemates or mixtures thereof, in-vivo-hydrolysableprecursors and pharmaceutically-acceptable salts of compounds of formulaI, solvated or unsolvated forms of compounds of formula I,pharmaceutical compositions and formulations containing them, methods ofusing them to treat diseases and conditions either alone or incombination with other therapeutically-active compounds or substances,processes and intermediates used to prepare them, uses of them asmedicaments, uses of them in the manufacture of medicaments and uses ofthem for diagnostic and analytic purposes.

DESCRIPTION OF PREFERRED EMBODIMENTS

In one aspect, the invention provides a compound of formula I, apharmaceutically acceptable salt thereof, diastereomers, enantiomers, ormixtures thereof:

wherein

Z is selected from O═ and S═;

R¹ is selected from C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,R⁵R⁶N—C₁₋₆alkyl, R⁵O—C₁₋₆alkyl, R⁵C(═O)N(—R⁶)—C₁₋₆alkyl,R⁵R⁶NS(═O)₂—C₁₋₆alkyl, R⁵CS(═O)₂N(—R)—C₁₋₆alkyl,R⁵R⁶NC(═O)N(—R⁷)—C₁₋₆alkyl, R⁵R⁶NS(═O)₂N(R⁷)—C₁₋₆alkyl,C₆₋₁₀aryl-C₁₋₆alkyl, C₆₋₁₀aryl-C(═O)—C₁₋₆alkyl,C₃₋₁₀cycloalkyl-C₁₋₆allyl, C₄₋₈cycloalkenyl-C₁₋₆alkyl,C₃₋₆heterocyclyl-C₁₋₆alkyl, C₃₋₆heterocyclyl-C(═O)—C₁₋₆alkyl,C₁₋₁₀hydrocarbylamino, R⁵R⁶N—, R⁵O—, R⁵C(═O)N(—R⁶)—, R R⁶NS(═O)₂—,R⁵CS(═O)₂N(—R⁶)—, R⁵R⁶NC(═O)N(—R⁷)—, R⁵R⁶NS(═O)₂N(R⁷)—, C₆₋₁₀aryl,C₆₋₁₀aryl-C(═O)—, C₃₋₁₀cycloalkyl, C₄₋₈cycloalkenyl, C₃₋₆heterocyclyland C₃₋₆heterocyclyl-C(═O)—; wherein said C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₆₋₁₀aryl-C₁₋₆alkyl, C₆₋₁₀aryl-C(═O)—C₁₋₆alkyl,C₃₋₁₀cycloalkyl-C₁₋₆alkyl, C₄₋₈cycloalkenyl-C₁₋₆alkyl,C₃₋₆heterocyclyl-C₁₋₆alkyl, C₃₋₆heterocyclyl-C(═O)—C₁₋₆alkyl,C₁₋₁₀hydrocarbylamino, C₆₋₁₀aryl, C₆₋₁₀aryl-C(═O)—, C₃₋₁₀cycloalkyl,C₄₋₈cycloalkenyl, C₃₋₆heterocyclyl or C₃₋₆heterocyclyl-C(═O)— used indefining R¹ is optionally substituted by one or more groups selectedfrom halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and—NR⁵R⁶;

R² is selected from the group consisting of C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀aklynyl, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₆alkyl,C₄₋₈cycloalkenyl-C₁₋₆alkyl, C₃₋₆heterocycloalkyl-C₁₋₆alkyl,C₄₋₈cycloalkenyl, R⁵R⁶N—, C₃₋₅heteroaryl, C₆₋₁₀aryl andC₃₋₆heterocycloalkyl, wherein said C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₆alkyl,C₄₋₈cycloalkenyl-C₁₋₆alkyl, C₃₋₆heterocycloalkyl-C₁₋₆alkyl,C₄₋₈cycloalkenyl, C₃₋₅heteroaryl, C₆₋₁₀aryl or C₃₋₆heterocycloalkyl usedin defining R² is optionally substituted by one or more groups selectedfrom halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and—NR⁵R⁶;

wherein R⁵, R⁶ and R⁷ are independently selected from —H, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, and a divalent C₁₋₆ group that together withanother divalent R⁵, R⁶ or R⁷ forms a portion of a ring; and

R³ is selected from R⁸, R⁸O—, and R⁸R⁹N—;

each of R⁴, R⁸ and R⁹ is independently selected from —H, C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₆alkyl,C₃₋₆heterocyclyl, C₆₋₁₀aryl, C₃₋₆heterocylcyl-C₁₋₆alkyl,C₆₋₁₀-aryl-C₁₋₆alkyl, and a divalent C₁₋₆group that together withanother divalent group selected from R⁴, R⁸ and R⁹ forms a portion of aring, wherein said C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₆alkyl, C₃₋₆heterocyclyl, C₆₋₁₀aryl,C₃₋₆heterocylcyl-C₁₋₆alkyl, C₆₋₁₀aryl-C₁₋₆alkyl, or divalent C₁₋₆groupis optionally substituted by one or more groups selected from halogen,cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and —NR⁵R⁶.

Particularly, the compounds of the present invention are those offormula I, wherein

Z is O═;

R¹ is selected from C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,R⁵R⁶N—C₁₋₄alkyl, R⁵O—C₁₋₄alkyl, R⁵C(═O)N(—R⁶)—C₁₋₄alkyl,phenyl-C₁₋₄alkyl, phenyl-C(═O)—C₁₋₄alkyl, C₃₋₁₀cycloalkyl-C₁₋₄alkyl,C₄₋₆cycloalkenyl-C₁₋₄alkyl, C₃₋₆heterocyclyl-C₁₋₄alkyl,C₃₋₆heterocyclyl-C(═O) —C₁₋₄alkyl, R⁵R⁶N—, R⁵O—, R⁵R⁶NS(═O)₂—,C₆₋₁₀aryl, C₆₋₁₀aryl-C(═O)—, C₃₋₁₀cycloalkyl, C₄₋₆cycloalkenyl,C₃₋₆heterocyclyl and C₃₋₆heterocyclyl-C(═O)—; wherein said C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, phenyl-C₁₋₄alkyl, phenyl-C(═O)—C₁₋₄alkyl,C₃₋₁₀cycloalkyl-C₁₋₄alkyl, C₄₋₆cycloalkenyl-C₁₋₄alkyl,C₃₋₆heterocyclyl-C₁₋₄alkyl, C₃₋₆heterocyclyl-C(═O)—C₁₋₄alkyl, C₆₋₁₀aryl,C₆₋₁₀aryl-C(═O)—, C₃₋₁₀cycloalkyl, C₄₋₆cycloalkenyl, C₃₋₆heterocyclyl orC₃₋₆heterocyclyl-C(═O)— used in defining R¹ is optionally substituted byone or more groups selected from halogen, cyano, nitro, methoxy, ethoxy,methyl, ethyl, hydroxy, and —NR⁵R⁶;

wherein R⁵ and R⁶ are independently selected from —H, C₁₋₆alkyl andC₂₋₆alkenyl;

R² is selected from the group consisting of C₁₋₆alkyl, C₂₋₆alkenyl,C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₄alkyl, C₄₋₆cycloalkenyl-C₁₋₄alkyl,C₃₋₆heterocycloalkyl-C₁₋₄alkyl, C₄₋₆cycloalkenyl, C₃₋₅heteroaryl,R⁵R⁶N—, phenyl and C₃₋₆heterocycloalkyl, wherein said C₁₋₆alkyl,C₂₋₆alkenyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₄alkyl,C₄₋₆cycloalkenyl-C₁₋₄alkyl, C₃₋₆heterocycloalkyl-C₁₋₄alkyl,C₄₋₆cycloalkenyl, C₃₋₅heteroaryl, phenyl or C₃₋₆heterocycloalkyl used indefining R² is optionally substituted by one or more groups selectedfrom halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy andamino; and

R³ is selected from R⁸, R⁸O—, R⁸HN— and R⁸R⁹N—;

R⁸ and R⁹ are independently selected from C₁₋₆alkyl, C₂₋₆alkenyl,C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₄alkyl, C₃₋₆heterocyclyl, phenyl,C₃₋₆heterocylcyl-C₁₋₄alkyl, and phenyl-C₁₋₄alkyl, wherein saidC₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₄alkyl,C₃₋₆heterocyclyl, phenyl, C₃₋₆heterocylcyl-C₁₋₄alkyl, orphenyl-C₁₋₄alkyl is optionally substituted by one or more groupsselected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl,hydroxy and amino; and

R⁴ is selected from —H, C₁₋₆alkyl and C₂₋₆alkenyl.

More particularly, the compounds of the present invention are those offormula I,

wherein Z is O═;

R¹ is selected from C₁₋₆-alkyl, C₂₋₆alkenyl, R⁵R⁶N—C₁₋₄alkyl,R⁵O—C₁₋₄alkyl, R⁵C(═O)N(—R)—C₁₋₄alkyl, phenyl-C₁₋₄alkyl,phenyl-C(═O)—C₁₋₄alkyl, C₃₋₁₀cycloalkyl-C₁₋₄alkyl,C₄₋₆cycloalkenyl-C₁₋₄alkyl, C₃₋₆heterocyclyl-C₁₋₄alkyl,C₃₋₆heterocyclyl-C(═O)—C₁₋₄alkyl, phenyl, C₃₋₁₀cycloalkyl,C₃₋₆heterocyclyl and C₃₋₆heterocyclyl-C(═O)—; wherein said C₁₋₆alkyl,C₂₋₆alkenyl, R⁵R⁶N—C₁₋₄alkyl, R⁵O—C₁₋₄alkyl, R⁵C(═O)N(—R⁶)—C₁₋₄alkyl,phenyl-C₁₋₄alkyl, phenyl-C(═O)—C₁₋₄alkyl, C₃₋₁₀cycloalkyl-C₁₋₄alkyl,C₄₋₆cycloalkenyl-C₁₋₄alkyl, C₃₋₆heterocyclyl-C₁₋₄alkyl,C₃₋₆heterocyclyl-C(═O)—C₁₋₄alkyl, phenyl, C₃₋₁₀cycloalkyl,C₃₋₆heterocyclyl or C₃₋₆ heterocyclyl-C(═O)— used in defining R¹ isoptionally substituted by one or more groups selected from halogen,cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and —NR⁵R⁶;

R² is selected from the group consisting of C₁₋₆alkyl, C₃₋₆cycloalkyl,R⁵R⁶N—, C₃₋₆cycloalkyl-C₁₋₄alkyl, C₃₋₆heterocycloalkyl-C₁₋₄alkyl,C₃₋₆heterocycloalkyl, C₃₋₅heteroaryl, and phenyl wherein said C₁₋₆alkyl,C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₄alkyl,C₃₋₆heterocycloalkyl-C₁₋₄alkyl, C₃₋₆heterocycloalkyl, C₃₋₅heteroaryl,and phenyl used in defining R² is optionally substituted by one or moregroups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl,ethyl, hydroxy and amino;

R⁵ and R⁶ are independently selected from —H, C₁₋₆alkyl and C₂₋₆alkenyl;and

R³ is selected from R⁸, R⁸O—, R⁸HN— and R⁸R⁹N—;

R⁸ and R⁹ are independently selected from C₁₋₆alkyl, C₂₋₆alkenyl,C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₄alkyl, C₃₋₅heterocyclyl, phenyl,C₃₋₅heterocylcyl-C₁₋₄alkyl, and phenyl-C₁₋₄alkyl, wherein saidC₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₄alkyl,C₃₋₅heterocyclyl, phenyl, C₃₋₅heterocylcyl-C₁₋₄alkyl, orphenyl-C₁₋₄alkyl is optionally substituted by one or more groupsselected from halogen, cyano, methoxy, methyl, and ethyl; and

R⁴ is selected from —H and C₁₋₄alkyl.

Most particularly, the compounds of the present invention are those offormula I, wherein

Z is O═;

R¹ is selected from cyclohexylmethyl, cyclopentylmethyl,cyclobutylmethyl, cyclopropylmethyl, ethyl, propyl, adamantyl,adamantylmethyl, allyl, isopentyl, benzyl, methoxyethyl,tetrahydropyranylmethyl, tetrahydrofuranylmethyl, cyclohexyloxy,cyclohexylamino, dimethylaminoethyl, 4-pyridylmethyl, 2-pyridylmethyl,1-pyrrolylethyl, 1-morpholinoethyl, 4,4-difluorocyclohexylmethyl,cyclohexylmethyl, 2-pyrrolidylmehtyl, N-methyl-2-pyrrolidylmethyl,2-piperidylmethyl, N-methyl-2-piperidylmethyl, 3-thienylmethyl,(2-nitrothiophene-5-yl)-methyl, (1-methyl-1H-imidazole-2-yl)methyl,(5-(acetoxymethyl)-2-furyl)methyl),(2,3-dihydro-1H-isoindole-1-yl)methyl, and 5-(2-methylthiazolyl);

R² is selected from t-butyl, n-butyl, 2-methyl-2-butyl, cyclohexyl,cyclohexylmethyl, n-pentyl, isopentyl, trifluoromethyl,1,1-difluoroethyl, N-piperidyl, dimethylamino, phenyl, pyridyl,tetrahydrofuranyl, tetrahydropyranyl, 2-methoxy-2-propyl andN-morpholinyl;

R³ is selected from methyl, ethyl, isopropyl, n-butyl, t-butyl,iso-butyl, phenyl, pyridyl, imidazolyl, naphthalenyl, isopropylamino and2-thienyl; and

R⁴ is selected from —H, methyl and ethyl.

It will be understood that when compounds of the present inventioncontain one or more chiral centers, the compounds of the invention mayexist in, and be isolated as, enantiomeric or diastereomeric forms, oras a racemic mixture. The present invention includes any possibleenantiomers, diastereomers, racemates or mixtures thereof, of a compoundof Formula I. The optically active forms of the compound of theinvention may be prepared, for example, by chiral chromatographicseparation of a racemate, by synthesis from optically active startingmaterials or by asymmetric synthesis based on the procedures describedthereafter.

It will also be appreciated that certain compounds of the presentinvention may exist as geometrical isomers, for example E and Z isomersof alkenes. The present invention includes any geometrical isomer of acompound of Formula I. It will further be understood that the presentinvention encompasses tautomers of the compounds of the formula I.

It will also be understood that certain compounds of the presentinvention may exist in solvated, for example hydrated, as well asunsolvated forms. It will further be understood that the presentinvention encompasses all such solvated forms of the compounds of theformula I.

Within the scope of the invention are also salts of the compounds of theformula I. Generally, pharmaceutically acceptable salts of compounds ofthe present invention may be obtained using standard procedures wellknown in the art, for example by reacting a sufficiently basic compound,for example an alkyl amine with a suitable acid, for example, HCl oracetic acid, to afford a physiologically acceptable anion. It may alsobe possible to make a corresponding alkali metal (such as sodium,potassium, or lithium) or an alkaline earth metal (such as a calcium)salt by treating a compound of the present invention having a suitablyacidic proton, such as a carboxylic acid or a phenol with one equivalentof an alkali metal or alkaline earth metal hydroxide or alkoxide (suchas the ethoxide or methoxide), or a by conventional purificationtechniques.

In one embodiment, the compound of formula I above may be converted to apharmaceutically acceptable salt or solvate thereof, particularly, anacid addition salt such as a hydrochloride, hydrobromide, phosphate,acetate, fumarate, maleate, tartrate, citrate, methanesulphonate orp-toluenesulphonate.

We have now found that the compounds of the invention have activity aspharmaceuticals, in particular as modulators or ligands such asagonists, partial agonists, inverse agonist or antagonists of CB1receptors. More particularly, the compounds of the invention exhibitselective activity as agonist of the CB1 receptors and are useful intherapy, especially for relief of various pain conditions such aschronic pain, neuropathic pain, acute pain, cancer pain, pain caused byrheumatoid arthritis, migraine, visceral pain etc. This list shouldhowever not be interpreted as exhaustive. Additionally, compounds of thepresent invention are useful in other disease states in whichdysfunction of CB1 receptors is present or implicated. Furthermore, thecompounds of the invention may be used to treat cancer, multiplesclerosis, Parkinson's disease, Huntington's chorea, Alzheimer'sdisease, anxiety disorders, gastrointestinal disorders andcardiovascular disorders.

Compounds of the invention are useful as immunomodulators, especiallyfor autoimmune diseases, such as arthritis, for skin grafts, organtransplants and similar surgical needs, for collagen diseases, variousallergies, for use as anti-tumour agents and anti viral agents.

Compounds of the invention are useful in disease states wheredegeneration or dysfunction of cannabinoid receptors is present orimplicated in that paradigm. This may involve the use of isotopicallylabelled versions of the compounds of the invention in diagnostictechniques and imaging applications such as positron emission tomography(PET).

Compounds of the invention are useful for the treatment of diarrhoea,depression, anxiety and stress-related disorders such as post-traumaticstress disorders, panic disorder, generalized anxiety disorder, socialphobia, and obsessive compulsive disorder, urinary incontinence,premature ejaculation, various mental illnesses, cough, lung oedema,various gastro-intestinal disorders, e.g. constipation, functionalgastrointestinal disorders such as Irritable Bowel Syndrome andFunctional Dyspepsia, Parkinson's disease and other motor disorders,traumatic brain injury, stroke, cardioprotection following myocardialinfarction, spinal injury and drug addiction, including the treatment ofalcohol, nicotine, opioid and other drug abuse and for disorders of thesympathetic nervous system for example hypertension.

Compounds of the invention are useful as an analgesic agent for useduring general anaesthesia and monitored anaesthesia care. Combinationsof agents with different properties are often used to achieve a balanceof effects needed to maintain the anaesthetic state (e.g. amnesia,analgesia, muscle relaxation and sedation). Included in this combinationare inhaled anaesthetics, hypnotics, anxiolytics, neuromuscular blockersand opioids.

Also within the scope of the invention is the use of any of thecompounds according to the formula I above, for the manufacture of amedicament for the treatment of any of the conditions discussed above.

A further aspect of the invention is a method for the treatment of asubject suffering from any of the conditions discussed above, whereby aneffective amount of a compound according to the formula I above, isadministered to a patient in need of such treatment.

Thus, the invention provides a compound of formula I, orpharmaceutically acceptable salt or solvate thereof, as hereinbeforedefined for use in therapy.

In a further aspect, the present invention provides the use of acompound of formula I, or a pharmaceutically acceptable salt or solvatethereof, as hereinbefore defined in the manufacture of a medicament foruse in therapy.

The compounds of the present invention are useful in therapy, especiallyfor the therapy of various pain conditions including, but not limitedto: acute pain, chronic pain, neuropathic pain, back pain, cancer pain,and visceral pain.

In use for therapy in a warm-blooded animal such as a human, thecompound of the invention may be administered in the form of aconventional pharmaceutical composition by any route including orally,intramuscularly, subcutaneously, topically, intranasally,intraperitoneally, intrathoracially, intravenously, epidurally,intrathecally, intracerebroventricularly and by injection into thejoints.

In one embodiment of the invention, the route of administration may beorally, intravenously or intramuscularly.

The dosage will depend on the route of administration, the severity ofthe disease, age and weight of the patient and other factors normallyconsidered by the attending physician, when determining the individualregimen and dosage level at the most appropriate for a particularpatient.

For preparing pharmaceutical compositions from the compounds of thisinvention, inert, pharmaceutically acceptable carriers can be eithersolid and liquid. Solid form preparations include powders, tablets,dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substances, which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, or table disintegrating agents; it can also be an encapsulatingmaterial.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided compound of the invention, or the activecomponent. In tablets, the active component is mixed with the carrierhaving the necessary binding properties in suitable proportions andcompacted in the shape and size desired.

For preparing suppository compositions, a low-melting wax such as amixture of fatty acid glycerides and cocoa butter is first melted andthe active ingredient is dispersed therein by, for example, stirring.The molten homogeneous mixture in then poured into convenient sizedmoulds and allowed to cool and solidify.

Suitable carriers are magnesium carbonate, magnesium stearate, talc,lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose,sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and thelike.

The term composition is also intended to include the formulation of theactive component with encapsulating material as a carrier providing acapsule in which the active component (with or without other carriers)is surrounded by a carrier which is thus in association with it.Similarly, cachets are included.

Tablets, powders, cachets, and capsules can be used as solid dosageforms suitable for oral administration.

Liquid form compositions include solutions, suspensions, and emulsions.For example, sterile water or water propylene glycol solutions of theactive compounds may be liquid preparations suitable for parenteraladministration. Liquid compositions can also be formulated in solutionin aqueous polyethylene glycol solution.

Aqueous solutions for oral administration can be prepared by dissolvingthe active component in water and adding suitable colorants, flavoringagents, stabilizers, and thickening agents as desired. Aqueoussuspensions for oral use can be made by dispersing the finely dividedactive component in water together with a viscous material such asnatural synthetic gums, resins, methyl cellulose, sodium carboxymethylcellulose, and other suspending agents known to the pharmaceuticalformulation art.

Depending on the mode of administration, the pharmaceutical compositionwill preferably include from 0.05% to 99% w (percent by weight), morepreferably from 0.10 to 50% w, of the compound of the invention, allpercentages by weight being based on total composition.

A therapeutically effective amount for the practice of the presentinvention may be determined, by the use of known criteria including theage, weight and response of the individual patient, and interpretedwithin the context of the disease which is being treated or which isbeing prevented, by one of ordinary skills in the art.

Within the scope of the invention is the use of any compound of formulaI as defined above for the manufacture of a medicament.

Also within the scope of the invention is the use of any compound offormula I for the manufacture of a medicament for the therapy of pain.

Additionally provided is the use of any compound according to Formula Ifor the manufacture of a medicament for the therapy of various painconditions including, but not limited to: acute pain, chronic pain,neuropathic pain, back pain, cancer pain, and visceral pain.

A further aspect of the invention is a method for therapy of a subjectsuffering from any of the conditions discussed above, whereby aneffective amount of a compound according to the formula I above, isadministered to a patient in need of such therapy.

Additionally, there is provided a pharmaceutical composition comprisinga compound of Formula I, or a pharmaceutically acceptable salt thereof,in association with a pharmaceutically acceptable carrier.

Particularly, there is provided a pharmaceutical composition comprisinga compound of Formula I, or a pharmaceutically acceptable salt thereof,in association with a pharmaceutically acceptable carrier for therapy,more particularly for therapy of pain.

Further, there is provided a pharmaceutical composition comprising acompound of Formula I, or a pharmaceutically acceptable salt thereof, inassociation with a pharmaceutically acceptable carrier use in any of theconditions discussed above.

In a further aspect, the present invention provides a method ofpreparing the compounds of the present invention.

In one embodiment the invention provides a process for preparing acompound of formula II,

comprising the step of reacting a compound of formula III,

with a compound of R³C(═O)X to form the compound of formula II,wherein

X is selected from —Cl, —Br, —I, —OH, —OCH₃ and —OCH₂CH₃;

R¹ is selected from C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,R⁵R⁶N—C₁₋₆alkyl, R⁵O—C₁₋₆alkyl, R⁵C(═O)N(—R⁶)—C₁₋₆alkyl,R⁵R⁶NS(═O)₂—C₁₋₆alkyl, R⁵CS(═O)₂N(—R⁶)—C₁₋₆alkyl,R⁵R⁶NC(═O)N(—R⁷)—C₁₋₆alkyl, R⁵R⁶NS(═O)₂N(R⁷)—C₁₋₆alkyl,C₆₋₁₀aryl-C₁₋₆alkyl, C₆₋₁₀aryl -C(═O)—C₁₋₆alkyl,C₃₋₁₀-cycloalkyl-C₁₋₆alkyl, C₄₋₈cycloalkenyl-C₁₋₆alkyl,C₃₋₆heterocyclyl-C₁₋₆alkyl, C₃₋₆heterocyclyl-C(═O)—C₁₋₆alkyl,C₁₋₁₀hydrocarbylamino, R⁵R⁶N—, R⁵O—, R⁵C(═O)N(—R⁶)—, R⁵R⁶NS(═O)₂—,R⁵CS(═O)₂N(—R⁶)—, R⁵R⁶NC(═O)N(—R⁷)—, R⁵R⁶NS(═O)₂N(R⁷)—, C₆₋₁₀aryl,C₆₋₁₀aryl-C(═O)—, C₃₋₁₀cycloalkyl, C₄₋₈cycloalkenyl, C₃₋₆heterocyclyland C₃₋₆heterocyclyl-C(═O)—; wherein said C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₆₋₁₀aryl-C₁₋₆alkyl, C₆₋₁₀aryl-C(═O)—C₁₋₆alkyl,C₃₋₁₀cycloalkyl-C₁₋₆alkyl, C₄₋₈cycloalkenyl-C₁₋₆alkyl,C₃₋₁₀heterocyclyl-C₁₋₆alkyl, C₃₋₆heterocyclyl-C(═O)—C₁₋₆alkyl,C₁₋₁₀hydrocarbylamino, C₆₋₁₀aryl, C₆₋₁₀aryl-C(═O)—, C₃₋₁₀cycloalkyl,C₄₋₈cycloalkenyl, C₃₋₆heterocyclyl or C₃₋₆heterocyclyl-C(═O)— used indefining R¹ is optionally substituted by one or more groups selectedfrom halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and—NR⁵R⁶;

R² is selected from the group consisting of C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₆aklyl,C₄₋₈cycloalkenyl-C₁₋₆alkyl, C₃₋₆heterocycloalkyl-C₁₋₆alkyl,C₄₋₈cycloalkenyl, R⁵R⁶N—, C₃₋₅heteroaryl, C₆₋₁₀aryl andC₃₋₆heterocycloalkyl, wherein said C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₆alkyl,C₄₋₈cycloalkenyl-C₁₋₆alkyl, C₃₋₆heterocycloalkyl-C₁₋₆alkyl,C₄₋₈cycloalkenyl, C₃₋₅heteroaryl, C₆₋₁₀aryl or C₃₋₆heterocycloalkyl usedin defining R² is optionally substituted by one or more groups selectedfrom halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy andamino;

wherein R⁵, R⁶ and R⁷ are independently selected from —H, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, and a divalent C₁₋₆group that together withanother divalent R⁵, R⁶ or R⁷ forms a portion of a ring;

R³ is selected from R⁸, R⁸O—, R⁸NH—, and R⁸R⁹N—;

R⁸ and R⁹ are independently selected from C₁₋₆alkyl, C₂₋₆alkenyl,C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₄alkyl, C₃₋₆heterocyclyl, phenyl,C₃₋₆heterocylcyl-C₁₋₄alkyl, and phenyl-C₁₋₄alkyl, wherein saidC₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₄alkyl,C₃₋₆heterocyclyl, phenyl, C₃₋₆heterocylcyl-C₁₋₄alkyl, orphenyl-C₁₋₄alkyl is optionally substituted by one or more groupsselected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl,hydroxy and amino; and

R⁴ is selected from —H, C₁₋₆alkyl and C₂₋₆alkenyl.

Particularly, the present invention provides a method of preparing acompound of formula II, wherein Z is O═;

R¹ is selected from cyclohexylmethyl, cyclopentylmethyl,cyclobutylmethyl, cyclopropylmethyl, ethyl, propyl, adamantyl,adamantylmethyl, allyl, isopentyl, benzyl, methoxyethyl,tetrahydropyranylmethyl, tetrahydrofuranylmethyl, cyclohexyloxy,cyclohexylamino, dimethylaminoethyl, 4-pyridylmethyl, 2-pyridylmethyl,1-pyrrolylethyl, 1-morpholinoethyl, 4,4-difluorocyclohexylmethyl,cyclohexylmethyl, 2-pyrrolidylmehtyl, N-methyl-2-pyrrolidylmethyl,2-piperidylmethyl, N-methyl-2-piperidylmethyl, 3-thienylmethyl,(2-nitrothiophene-5-yl)-methyl, (1-methyl-1H-imidazole-2-yl)methyl,(5-(acetoxymethyl)-2-furyl)methyl),(2,3-dihydro-1H-isoindole-1-yl)methyl, and 5-(2-methylthiazolyl);

R² is selected from t-butyl, n-butyl, 2-methyl-2-butyl, cyclohexyl,cyclohexylmethyl, n-pentyl, isopentyl, trifluoromethyl,1,1-difluoroethyl, N-piperidyl, dimethylamino, phenyl, pyridyl,tetrahydrofuranyl, tetrahydropyranyl, 2-methoxy-2-propyl andN-morpholinyl;

R³ is selected from methyl, ethyl, isopropyl, n-butyl, t-butyl,iso-butyl, phenyl, pyridyl, imidazolyl, naphthalenyl, isopropylamino and2-thienyl; and

R⁴ is selected from —H, methyl and ethyl.

In a further aspect, the present invention provides a method forpreparing a compound of formula IV,

comprising the step of reacting a compound of formula V,

with a reducing agent selected from AlH₃, NaBH₄, NaBH(O-iPr)₃, andLiAlH₄,wherein

R¹ is selected from C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,R⁵R⁶N—C₁₋₆alkyl, R⁵O—C₁₋₆alkyl, R⁵C(═O)N(—R⁶)—C₁₋₆alkyl,R⁵R⁶NS(═O)₂—C₁₋₆alkyl, R⁵CS(═O)₂N(—R⁶)—C₁₋₆alkyl,R⁵R⁶NC(═O)N(—R⁷)—C₁₋₆alkyl, R⁵R⁶NS(═O)₂N(R⁷)—C₁₋₆alkyl,C₆₋₁₀aryl-C₁₋₆alkyl, C₆₋₁₀aryl -C(═O)—C₁₋₆alkyl,C₃₋₁₀cycloalkyl-C₁₋₆alkyl, C₄₋₈cycloalkenyl-C₁₋₆alkyl,C₃₋₆heterocyclyl-C₁₋₆alkyl, C₃₋₆heterocyclyl-C(═O)—C₁₋₆alkyl,C₁₋₁₀hydrocarbylamino, R⁵R⁶N—, R⁵O—, R⁵C(═O)N(—R⁶)—, R⁵R⁶NS(═O)₂—,R⁵CS(═O)₂N(—R⁶)—, R⁵R⁶NC(═O)N(—R⁷)—, R⁵R⁶NS(═O)₂N(R⁷)—, C₆₋₁₀aryl,C₆₋₁₀aryl-C(═O)—, C₃₋₁₀cycloalkyl, C₄₋₈cycloalkenyl, C₃₋₆heterocyclyland C₃₋₆heterocyclyl-C(═O)—; wherein said C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₆₋₁₀aryl-C₁₋₆alkyl, C₆₋₁₀aryl-C(═O)—C₁₋₆alkyl,C₃₋₁₀cycloalkyl-C₁₋₆alkyl, C₄₋₈cycloalkenyl-C₁₋₆alkyl,C₃₋₆heterocyclyl-C₁₋₆alkyl, C₃₋₆heterocyclyl-C(═O)—C₁₋₆alkyl,C₁₋₁₀hydrocarbylamino, C₆₋₁₀aryl, C₆₋₁₀aryl-C(═O)—, C₃₋₁₀cycloalkyl,C₄₋₈cycloalkenyl, C₃₋₆heterocyclyl or C₃₋₆heterocyclyl-C(═O)— used indefining R¹ is optionally substituted by one or more groups selectedfrom halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy andamino;

R² is selected from the group consisting of C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₆alkyl,C₄₋₈cycloalkenyl-C₁₋₆alkyl, C₃₋₆heterocycloalkyl-C₁₋₆alkyl,C₄₋₈cycloalkenyl, R⁵R⁶N—, C₃₋₅heteroaryl, C₁₋₁₀aryl andC₃₋₆heterocycloalkyl, wherein said C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₆alkyl,C₄₋₈cycloalkenyl-C₁₋₆alkyl, C₃₋₆heterocycloalkyl-C₁₋₆alkyl,C₄₋₈cycloalkenyl, C₃₋₅-heteroaryl, C₆₋₁₀aryl or C₃₋₆heterocycloalkylused in defining R² is optionally substituted by one or more groupsselected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl,hydroxy, and —NR⁵R⁶;

wherein R⁵, R⁶ and R⁷ are independently selected from —H, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, and a divalent C₁₋₆group that together withanother divalent R⁵, R⁶ or R⁷ forms a portion of a ring; and

R¹⁰ is selected from —H, C₁₋₆alkyl, and C₁₋₆alkenyl.

Particularly, the present invention provides a method of preparing acompound of formula IV, wherein

R¹ is selected from cyclohexylmethyl, cyclopentylmethyl,cyclobutylmethyl, cyclopropylmethyl, ethyl, propyl, adamantyl,adamantylmethyl, allyl, isopentyl, benzyl, methoxyethyl,tetrahydropyranylmethyl, tetrahydrofuranylmethyl, cyclohexyloxy,cyclohexylamino, dimethylaminoethyl, 4-pyridylmethyl, 2-pyridylmethyl,1-pyrrolylethyl, 1-morpholinoethyl, 4,4-difluorocyclohexylmethyl,cyclohexylmethyl, 2-pyrrolidylmehtyl, N -methyl-2-pyrrolidylmethyl,2-piperidylmethyl, N-methyl-2-piperidylmethyl, 3-thienylmethyl,(2-nitrothiophene-5-yl)-methyl, (1-methyl-1H-imidazole-2-yl)methyl,(5-(acetoxymethyl)-2-furyl)methyl),(2,3-dihydro-1H-isoindole-1-yl)methyl, and 5-(2-methylthiazolyl);

R² is selected from t-butyl, n-butyl, 2-methyl-2-butyl, cyclohexyl,cyclohexylmethyl, n-pentyl, isopentyl, trifluoromethyl,1,1-difluoroethyl, N-piperidyl, dimethylamino, phenyl, pyridyl,tetrahydrofuranyl, tetrahydropyranyl, 2-methoxy-2-propyl andN-morpholinyl; and

R¹⁰ is selected from —H and C₁₋₆alkyl.

Compounds of the present invention may be prepared according to thesynthetic routes as depicted in Schemes 1 and 2 using one or moremethods disclosed above.

BIOLOGICAL EVALUATION

hCB₁ and hCB₂ receptor binding

Human CB₁ receptor from Receptor Biology (hCB1) or human CB₂ receptorfrom BioSignal (hCB2) membranes are thawed at 37° C., passed 3 timesthrough a 25-gauge blunt-end needle, diluted in the cannabinoid bindingbuffer (50 mM Tris, 2.5 mM EDTA, 5 mM MgCl₂, and 0.5 mg/mL BSA fattyacid free, pH 7.4) and aliquots containing the appropriate amount ofprotein are distributed in 96-well plates. The IC₅₀ of the compounds ofthe invention at hCB₁ and hCB₂ are evaluated from 10-point dose-responsecurves done with ³H—CP55,940 at 20000 to 25000 dpm per well (0.17-0.21nM) in a final volume of 300 μl. The total and non-specific binding aredetermined in the absence and presence of 0.2 μM of HU210 respectively.The plates are vortexed and incubated for 60 minutes at roomtemperature, filtered through Unifilters GF/B (presoaked in 0.1%polyethyleneimine) with the Tomtec or Packard harvester using 3 mL ofwash buffer (50 mM Tris, 5 mM MgCl₂, 0.5 mg BSA pH 7.0). The filters aredried for 1 hour at 55° C. The radioactivity (cpm) is counted in aTopCount (Packard) after adding 65 μL/well of MS-20 scintillationliquid.

hCB₁ and hCB₂ GTPγS binding

Human CB₁ receptor from Receptor Biology (hCB1) or human CB₂ receptormembranes (BioSignal) are thawed at 37° C., passed 3 times through a25-gauge blunt-end needle and diluted in the GTPγS binding buffer (50 mMHepes, 20 mM NaOH, 100 mM NaCl, 1 mM EDTA, 5 mM MgCl₂, pH 7.4, 0.1%BSA). The EC₅₀ and E_(max) of the compounds of the invention areevaluated from 10-point dose-response curves done in 300 μl with theappropriate amount of membrane protein and 100000-130000 dpm of GTPg³⁵Sper well (0.11-0.14 nM). The basal and maximal stimulated binding isdetermined in absence and presence of 1 μM (hCB₂) or 10 μM (hCB₁) Win55,212-2 respectively. The membranes are pre-incubated for 5 minuteswith 56.25 μM (hCB2) or 112.5 μM (hCB₁) GDP prior to distribution inplates (15 μM (hCB₂) or 30 μM (hCB₁) GDP final). The plates are vortexedand incubated for 60 minutes at room temperature, filtered on UnifiltersGF/B (presoaked in water) with the Tomtec or Packard harvester using 3ml of wash buffer (50 mM Tris, 5 mM MgCl₂, 50 mM NaCl, pH 7.0). Thefilters are dried for 1 hour at 55° C. The radioactivity (cpm) iscounted in a TopCount (Packard) after adding 65 μl/well of MS-20scintillation liquid. Antagonist reversal studies are done in the sameway except that (a) an agonist dose-response curve is done in thepresence of a constant concentration of antagonist, or (b) an antagonistdose-response curve is done in the presence of a constant concentrationof agonist.

Based on the above assays, the dissociation constant (Ki) for aparticular compound of the invention towards a particular receptor isdetermined using the following equation:Ki=IC ₅₀/(1+[rad]/Kd),

Wherein IC₅₀ is the concentration of the compound of the invention atwhich 50% displacement has been observed;

[rad] is a standard or reference radioactive ligand concentration atthat moment; and

Kd is the dissociation constant of the radioactive ligand towards theparticular receptor.

Using above-mentioned assays, the Ki towards human CB₁ receptors formost compounds of the invention is measured to be in the range of36-5700 nM. The Ki towards human CB₂ receptors for most compounds of theinvention is measured to be in the range of about 1.6-36 nM.

Using the above described assays, the IC₅₀ towards CB₁ receptor for mostof the compounds of the present invention is generally in the range of14.1 nM-3920.3 nM.

EXAMPLES

The invention will further be described in more detail by the followingExamples which describe methods whereby compounds of the presentinvention may be prepared, purified, analyzed and biologically tested,and which are not to be construed as limiting the invention.

Example 1N-[2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]-N-methylthiophene-2-carboxamide

Step A.N-[2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]-N-methylthiophene-2-carboxamide

2-tert-Butyl-1-(cyclohexylmethyl)-N-methyl-1H-benzimidazol-5-amine (30mg, 0.100 mmol) (for preparation, see the following steps B to F) and acatalytic amount of DMAP were dissolved in 3 mL of dichloromethane.2-Thiophenecarbonyl chloride (0.013 mL, 0.120 mmol) was added and thesolution was stirred at RT overnight. The solution was concentrated andthe product was purified by reversed-phase HPLC using 20-80% CH₃CN/H₂Oand then lyophilized to afford the desired title compound as thecorresponding TFA salt. Yield: 35 mg (67%); ¹H NMR (400 MHz,METHANOL-D₄) δ 1.22 (m, 5H), 1.61 (m, 1H), 1.63 (m, J=1.17 Hz, 1H), 1.65(s, 9H), 1.68 (m, 1H), 1.75 (m, 2H), 2.10 (m, 1H), 3.48 (s, 3H), 4.46(d, J=7.62 Hz, 2H), 6.79 (dd, J=4.98, 3.81 Hz, 1H), 6.85 (dd, J=3.91,1.17 Hz, 1H), 7.45 (dd, J=5.08, 1.17 Hz, 1H), 7.53 (dd, J=8.88, 2.05 Hz,1H), 7.68 (d, J=1.95 Hz, 1H), 7.95 (d, J=8.79 Hz, 1H); MS (ESI) (M+H)⁺:410.2.

Step B. Methyl(4-fluoro-3-nitrophenyl)carbamate

Methyl chloroformate (13.2 mL, 170.2 mmol) was added dropwise to a cold(0° C.) dichloromethane (200 mL) solution of 4-fluoro-3-nitro aniline(24.15 g, 154.7 mmol) and DIPEA (35 mL, 201 mmol). The reaction mixturewas stirred at rt overnight. The solution was then diluted with 200 mLof dichloromethane and washed with 2M HCl, brine and dried overanhydrous MgSO₄. The solvent was concentrated and the product directlyused in the next step without further purification. Yield: 35.5 g (99%);¹H NMR (400 MHz, CHLOROFORM-D) δ 3.81 (s, 3H), 7.02 (s, 1H), 7.23 (m,1H), 7.72 (d, J-=8.59 Hz, 1H), 8.17 (dd, J=6.35, 2.64 Hz, 1H).

Step C. Methyl{4-[(cyclohexylmethyl)amino]-3-nitrophenyl}carbamate

Methyl(4-fluoro-3-nitrophenyl)carbamate (1.00 g, 4.67 mmol) andcyclohexylmethyl amine (0.730 mL, 5.60 mmol) were stirred in EtOH (20mL) containing TEA (1.0 mL, 7.00 mmol) at 75° C. for 24 h. The solventwas concentrated. The residue was dissolved in EtOAc and washed with 5%KHSO₄ aqueous solution, saturated NaHCO₃ aqueous solution, brine anddried over anhydrous MgSO₄. The crude product was purified by flashchromatography using 4:1/hexanes:EtOAc on silica gel. Yield: 1.05 g(73%); ¹H NMR (400 MHz, CHLOROFORM-D) δ 1.04 (m, 2H), 1.25 (m, 3H), 1.69(m, 2H), 1.77 (m, 2H), 1.83 (m, 1H), 1.86 (m, 1H), 3.14 (m, 2H), 3.78(s, 3H), 6.46 (m, 1H), 6.84 (d, J=9.37, 1H), 7.63 (m, 1H), 8.05 (d,J=2.54 Hz, 1H), 8.09 (m, 1H).

Step D. Methyl {3-amino-4-[(cyclohexylmethyl)amino]phenyl}carbamate

Methyl {4-[(cyclohexylmethyl)amino]-3-nitrophenyl}carbamate (1.05 g,3.42 mmol) was dissolved in 30 mL of EtOAc containing a catalytic amountof 10% Pd/C. The solution was shaken in a Parr hydrogenation apparatusunder H₂ atmosphere (40 psi) at RT overnight The solution was filteredthrough Celite and the solvent was evaporated. The product was directlyused in the next step without further purification. Yield: 950 mg (99%).MS (ESI) (M+H)⁺: 277.9.

Step E.Methyl[2-tert-butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]carbamate

Methyl {3-amino-4-[(cyclohexylmethyl)amino]phenyl}carbamate (950 mg,3.43 mmol) and DMAP (100 mg, 0.858 mmol) were dissolved in 25 mL ofdichloromethane. Trimethylacetyl chloride (0.460 mL, 3.77 mmol) wasadded dropwise and the solution stirred at RT for 1 h. The solvent wasconcentrated. The residue was divided in two and each of them dissolvedin 3 mL of glacial AcOH in a sealed tube. The solutions were heated at150° C. using a Personal Chemistry Smith Synthesizer microwaveinstrument for three intervals of 30 min (3×30 min). The two tubes werecombined and the solvent was evaporated. The residue was dissolved inEtOAc and washed with saturated NaHCO₃ aqueous solution, brine and driedover anhydrous MgSO₄. The crude product was purified by flashchromatography using 3:1/dichloromethane:diethyl ether on silica gel.Yield: 656 mg (56%); ¹H NMR (400 MHz, CHLOROFORM-D) δ 1.09 (m, 2H), 1.16(m, 4H), 1.54 (s, 9H), 1.65 (m, 1H), 1.62 (m, 1H), 1.70 (m, J=1.56 Hz,2H), 1.73 (dd, J=5.96, 3.22 Hz, 2H), 2.02 (m, 1H), 3.78 (s, 3H), 4.10(d, J=7.42 Hz, 2H), 6.64 (m, 1H), 7.25 (d, J=8.79 Hz, 1H), 7.39 (m, 1H),7.59 (d, J=1.76 Hz, 1H).

Step F.2-tert-Butyl-1-(cyclohexylmethyl)-N-methyl-1H-benzimidazol-5-amine

Methyl[2-tert-butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]carbamate(650 mg, 1.89 mmol) was dissolved in 20 mL of THF at 0° C. undernitrogen. 1M HCl/ether (2.65 mL, 2.65 mmol) was added dropwise and thesolution stirred at 0° C. for 15 min. LiAlH₄ (360 mg, 9.45 mmol) wasthen slowly added and the solution stirred at RT overnight. The reactionmixture was quenched at 0° C. by addition of MeOH (5 mL) followed bywater (10 mL). The solution was diluted with EtOAc and washed withsaturated NaHCO₃ aqueous solution, brine and dried over anhydrous MgSO₄.The solvent was evaporated and the product was used directly in the nextstep without further purification. Yield: 544 mg (96%). ¹H NMR (400 MHz,CHLOROFORM-D) δ 1.08 (m, 2H), 1.17 (m, 3H), 1.53 (s, 9H), 1.64 (s, 2H),1.67 (s, 2H), 1.72 (m, 2H), 2.02 (m, 1H), 2.86 (s, 3H), 4.06 (d, J=7.42Hz, 2H), 6.60 (dd, J=8.69, 2.25 Hz, 1H), 6.99 (d, J=2.15 Hz, 1H), 7.12(d, J=8.59 Hz, 1H).

Example 2N-[2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]-N,2,2-trimethylpropanamide

Following the same procedure used in Example 1, Step A, using2-tert-butyl-1-(cyclohexylmethyl)-N-methyl-1H-benzimidazol-5-amine (40mg, 0.134 mmol) and trimethylacetyl chloride (0.021 mL, 0.174 mmol) in 3mL of dichloromethane. The product was purified by reversed-phase HPLCusing 20-80% CH₃CN/H₂O on a C-18 column and then lyophilized to affordthe desired title compound as the corresponding TFA salt. Yield: 60 mg(90%); ¹H NMR (400 MHz, METHANOL-D₄) δ 1.07 (s, 9H), 1.23 (m, 5H), 1.63(m, 2H), 1.66 (s, 10H), 1.76 (m, 2H), 2.11 (m, 1H), 3.28 (s, 3H), 4.47(d, J=7.62 Hz, 2H), 7.51 (dd, J=8.79, 1.95 Hz, 1H), 7.65 (d, J=1.37 Hz,1H), 7.96 (d, J=8.98 Hz, 1H); MS (ESI) (M+H)⁺: 384.3; Anal. Calcd forC₂₄H₃₇N₃O+1.7 TFA+0.6H₂O: C, 55.95; H, 6.84; N, 7.14. Found: C, 55.92;H, 6.81; N, 7.07.

Example 3N-[2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]-N,2-dimethylpropanamide

Following the same procedure used in Example 1, Step A, using2-tert-butyl-1-(cyclohexylmethyl)-N-methyl-1H-benzimidazol-5-amine (40mg, 0.134 mmol) and isobutyryl chloride (0.018 mL, 0.174 mmol) in 3 mLof dichloromethane. The product was purified by reversed-phase HPLCusing 20-80% CH₃CN/H₂O on a C-18 column and then lyophilized to affordthe desired title compound as the corresponding TFA salt. Yield: 58 mg(90%); ¹H NMR (400 MHz, METHANOL-D₄) δ 0.99 (s, 6H), 1.24 (m, 5H), 1.65(m, 2H), 1.66 (s, 10H), 1.76 (s, 2H), 2.11 (m, 1H), 2.46 (m, 1H), 3.27(s, 3H), 4.47 (d, J=7.62 Hz, 2H), 7.52 (d, J=8.59 Hz, 1H), 7.67 (s, 1H),7.99 (d, J=8.79 Hz, 1H); MS (ESI) (M+H)⁺: 370.2; Anal. Calcd forC₂₃H₃₅N₃O+1.7 TFA+0.3H₂O: C, 55.75; H, 6.61; N, 7.39. Found: C, 55.77;H, 6.52; N, 7.45.

Example 4N-[2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]-N,3-dimethylbutanamide

Following the same procedure used in Example 1, Step A, using2-tert-butyl-1-(cyclohexylmethyl)-N-methyl-1H-benzimidazol-5-amine (30mg, 0.100 mmol) and isovaleryl chloride (0.016 mL, 0.130 mmol) in 3 mLof dichloromethane. The product was purified by reversed-phase HPLCusing 20-80% CH₃CN/H₂O on a C-18 column and then lyophilized to affordthe desired title compound as the corresponding TFA salt. Yield: 40 mg(80%); ¹H NMR (400 MHz, METHANOL-D₄) δ 0.79 (brs, 6H), 1.22 (brs, 6H),1.63 (s, 13H), 1.75 (brs, 1H), 1.97 (m, 1H), 2.03 (m, 1H), 2.10 (m, 1H),3.27 (s, 3H), 4.41 (d, J=7.42 Hz, 2H), 7.40 (dd, J=1.66, 8.88 Hz, 1H),7.58 (s, 1H), 7.88 (d, J=8.79 Hz, 1H); MS (ESI) (M+H)⁺: 384.3; Anal.Calcd for C₂₄H₃₇N₃O+1.0 TFA+0.3H₂O: C, 62.08; H, 7.73; N, 8.35. Found:C, 62.18; H, 7.57; N, 8.36.

Example 5N-[2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]-N′-isopropyl-N-methylurea

Following the same procedure used in Example 1, Step A, using2-tert-butyl-1-(cyclohexylmethyl)-N-methyl-1H-benzimidazol-5-amine (40mg, 0.134 mmol) and isopropyl isocyanate (0.015 mL, 0.161 mmol) in 5 mLof dichloromethane. The product was purified by reversed-phase HPLCusing 20-80% CH₃CN/H₂O on a C-18 column and then lyophilized to affordthe desired title compound as the corresponding TFA salt. Yield: 54 mg(81%); ¹H NMR (400 MHz, METHANOL-D₄) δ 1.10 (d, J=6.44 Hz, 6H), 1.22 (m,5H), 1.63 (m, 2H), 1.66 (s, 9H), 1.67 (m, 1H), 1.75 (m, 2H), 2.11 (m,1H), 3.28 (s, 3H), 3.90 (q, J=6.59 Hz, 1H), 4.45 (d, J=7.62 Hz, 2H),7.47 (dd, J=8.98, 1.95 Hz, 1H), 7.60 (d, J=1.56 Hz, 1H), 7.89 (d, J=8.98Hz, 1H); MS (ESI) (M+H)⁺: 385.2; Anal. Calcd for C₂₃H₃N₄O+1.5TFA+0.4H₂O: C, 55.49; H, 6.86; N, 9.95. Found: C, 55.42; H, 6.83; N,9.98.

Example 6N-[1-(Cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazol-5-yl]acetamide

Step A.N-[1-(Cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazol-5-yl]acetamide

DMAP (0.65 g, 5.3 mmol) was added to a suspension ofN-{3-amino-4-[cyclohexylmethyl)amino]phenyl}acetamide (2.09 g, 8.0 mmol)(for preparation, see the following steps B, C and D) in dichloromethane(40 mL) at −10° C., followed by addition of 2,2-dimethylbutyryl chloride(1.51 g, 11.2 mmol). The resulting mixture was stirred overnight at roomtemperature. After evaporation of the solvent, 4.14 g of a brown solidwas obtained, which was consistent with the desired coupling product. MS(ESI) (M+H)⁺=360.07.

308 mg of the above crude product was dissolved in 1,2-dichloroethane (5mL) in a Teflon-capped test tube. The vessel was irradiated by microwavefor 3 h at 170° C. The mixture was diluted with EtOAc (100 mL), washedwith 2N NaOH aqueous solution (10 mL), saturated NaCl aqueous solution(10 mL) and dried over Na₂SO₄. After filtration and evaporation, theresidue was purified by MPLC (EtOAc as eluent on silica gel) to give thedesired title compound as a light yellow solid (111.0 mg, 55%). ¹H NMR(400 MHz, CD₃OD): δ 0.84 (t, J=7.52 Hz, 3H), 1.25 (m, 5H), 1.63 (m, 2H),1.66 (s, 6H), 1.70 (m, 1H), 1.77 (m, 2H), 2.01 (q, J=7.42 Hz, 2H), 2.10(m, 1H), 2.18 (s, 3H), 4.44 (d, J=7.81 Hz, 2H), 7.50 (dd, J=8.98, 1.95Hz, 1H), 7.84 (d, J=9.18 Hz, 1H), 8.44 (d, J=1.76 Hz, 1H). MS (ESI)(M+H)⁺: 342.05. Anal. Calcd for C₂₁H₃₁N₃O+1.10 TFA+0.40H₂O (474.13): C,58.77; H, 6.99; N, 8.66. Found: C, 58.86; H, 6.90; N, 8.91.

Step B. N(4-fluoro-3-nitrophenyl)acetamide

4-Fluoro-3-nitro-aniline (45.0 g, 288.2 mmol) was added portionwise toacetic anhydride (150 mL) at room temperature. The reaction mixture wasstirred at room temperature for 2 h. The white solid was collected anddried in vacuo to give the desired title compound (42.0 g, 70%).

¹H NMR (400 MHz, CDCl₃): δ 2.23 (s, 3H), 7.26 (m, 1H), 7.50 (s broad,1H), 7.87 (m, 1H), 8.23 (dd, J=6.44, 2.73 Hz, 1H).

Step C. N-{4[(cyclohexylmethyl)amino]-3-nitrophenyl}acetamide

Cyclohexylmethylamine (2.86 mL, 2.49 g, 22.0 mmol) was added to amixture of N-(4-fluoro-3-nitrophenyl)acetamide (3.96 g, 20.0 mmol) andsodium carbonate (4.66 g, 44 mmol) in EtOH (50 mL) at room temperature.The reaction mixture was heated for 48 h at 60° C., and diluted with H₂O(800 mL). The orange solid was precipitated out and collected to givethe desired title product (6.60 g, 100%). MS (ESI) (M+H)⁺: 292.32.

Step D. N-{3-amino-4[(cyclohexylmethyl)amino]phenyl}acetamide

The above crude product(N-{4-[(cyclohexylmethyl)amino]-3-nitrophenyl}acetamide) washydrogenated in ethyl acetate (300 mL) catalyzed by 10% Pd/C (0.5 g) at20-30 psi H₂ in Parr shaker for 4.5 h at room temperature. Afterfiltration through celite and concentration, 5.08 g (97%) of a purplesolid was obtained. which was used in the next step without furtherpurification. ¹H NMR (400 MHz, CDCl₃): δ 1.00 (m, 2H), 1.24 (m, 3H),1.59 (m, 2H), 1.72 (m, 2H), 1.84 (m, 2H), 2.13 (s, 3H), 2.91 (d, J=6.64Hz, 2H), 3.37 (s broad, 3H), 6.56 (d, J=8.40 Hz, 1H), 6.69 (dd, J=8.30,2.25 Hz, 1H), 6.98 (s, 1H), 7.12 (d, J=2.34 Hz, 1H). MS (ESI) (M+H)⁺:262.31.

Example 7N-[1-(Cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazol-5-yl]-N′-isopropylurea

Step A.N-[1-(cyclohexylmethyl)-2-(1,1-dimethylpropyl-1H-benzimidazol-5-yl]-N′-isopropylurea

A mixture of1-(cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazol-5-aminehydrochloride (48.5 mg, 0.127 mmol), diisopropylethylamine (148 mg, 200uL, 1.15 mmol) and isopropylisocynate (0.5 mL) in 1,2-dichloroethane (5mL) was heated for 2 h at 60° C. Upon evaporation of the solvent, theresidue was treated with 2N NaOH aqueous solution (5 mL), extracted withEtOAc (3×20 mL). The combined organic phases were washed with saturatedNaCl aqueous solution (10 mL) and dried over Na₂SO₄. After filtrationand evaporation, the residue was purified by MPLC (EtOAc as eluent onsilica gel) to give the desired title compound as a syrup (34.8 mg,71%). ¹H NMR (400 MHz, CD₃OD): δ 0.84 (t, J=7.52 Hz, 3H), 1.20 (d,J=6.44 Hz, 6H), 1.25 (m, 5H), 1.63 (m, 2H), 1.66 (s, 6H), 1.70 (m, 1H),1.78 (m, 2H), 2.00 (q, J=7.42 Hz, 2H), 2.10 (m, 1H), 3.91 (m, 1H), 4.42(d, J=7.62 Hz, 2H), 7.28 (m, 1H), 7.76 (d, J=9.18 Hz, 1H), 8.18 (d,J=1.56 Hz, 1H). MS (ESI) (M+H)⁺: 385.2. Anal. Calcd for C₂₃H₃₆N₄O+1.20TFA+0.80H₂O (535.81): C, 56.94; H, 7.30; N, 10.46. Found: C, 56.90; H,7.27; N, 10.27.

Step B.1-(Cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazol-5-amine

N-[1-(Cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazol-5-yl]acetamide(105.4 mg, 0.309 mmol) was dissolved in ethanol (3 mL) and 2N HClaqueous solution (2 mL) in a Teflon-capped test tube. The vessel wasirradiated by microwave for 45 min. at 120° C. After evaporation anddrying in vacuo, 117.8 mg (100%) of the title compound was obtained as agrey white solid. ¹H NMR (400 MHz, CD₃CD): δ 0.87 (t, J=7.52 Hz, 3H),1.27 (m, 5H), 1.66 (m, 3H), 1.71 (s, 6H), 1.78 (m, 2H), 2.05 (q, J=7.42Hz, 2H), 2.13 (m, 1H), 4.53 (d, J=7.62 Hz, 2H), 7.66 (dd, J=8.79, 1.56Hz, 1H), 7.97 (d, J=1.76 Hz, 1H), 8.17 (d, J=8.79 Hz, 1H). MS (ESI)(M+H)⁺: 300.05.

Example 8N-[1-(Cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazol-5-yl]-2,2-dimethylbutanamide

2,2-Dimethylbutyryl chloride (24.6 mg, 0.18 mmol) was added to a mixtureof 1-(cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazol-5-aminehydrochloride (65.0 mg, 0.15 mmol) (for preparation see in Example 7,step B) and DMAP (73.3 mg, 0.60 mmol) in acetonitrile (5 mL) at 0° C.The mixture was stirred for 6 h at room temperature, diluted with EtOAc(50 mL), washed with saturated NaHCO₃ aqueous solution (10 mL),saturated NaCl aqueous solution (10 mL) and dried over Na₂SO₄. Afterfiltration and evaporation, the residue was purified by MPLC (EtOAc aseluent on silica gel) to give the desired title compound as a syrup(51.6 mg, 87%). ¹H NMR (400 MHz, CD₃OD): δ 0.84 (t, J=7.52 Hz, 3H), 0.91(t, J=7.52 Hz, 3H), 1.25 (m, 5H), 1.28 (s, 6H), 1.64 (m, 3H), 1.67 (s,6H), 1.72 (q, J=7.49 Hz, 2H), 1.78 (m, 2H), 2.02 (q, J=7.49 Hz, 2H),2.13 (m, 1H), 4.45 (d, J=7.62 Hz, 2H), 7.64 (dd, J=8.98, 1.76 Hz, 1H),7.85 (d, J=9.18 Hz, 1H), 8.34 (s, 1H). MS (ESI) (M+H)⁺: 398.3. Anal.Calcd for C₂₅H₃₉N₃O+1.50 TFA+0.70H₂O (581.25): C, 57.86; H, 7.27; N,7.23. Found: C, 57.90; H, 7.19; N, 7.34.

Example 9N-[2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]acetamide

Following the same procedure of Example 6, a mixture ofN-{3-amino-4-[(cyclohexylmethyl)amino]phenyl}acetamide (1.57 g, 6.0mmol) (for preparation see in Example 6, step D) and DMAP (0.15 g, 1.2mmol) in dichloromethane (70 mL) was treated with trimethylacetylchoride (0.83 g, 6.6 mmol) at −10° C. After evaporation of the solvent,the residue was dissolved in 1,2-dichloroethane (40 mL) and then dividedinto eight Teflon-capped test tubes. The vessels were irradiated bymicrowave for 2 h at 170° C. After purification by MPLC (EtOAc as eluenton silica gel), the desired title compound was obtained as a white solid(1.42 g, 72%). ¹H NMR (400 MHz, CD₃OD): δ 1.24 (m, 5H), 1.64 (m, 2H),1.67 (s, 9H), 1.70 (m, 1H), 1.77 (m, 2H), 2.12 (m, 1H), 2.18 (s, 3H),4.45 (d, J=7.62 Hz, 2H), 7.50 (m, 1H), 7.84 (d, J=8.98 Hz, 1H), 8.43 (d,J=1.95 Hz, 1H). MS (ESI) (M+H)⁺: 328.3. Anal. Calcd for C₂₀H₂₉N₃O+1.20TFA+0.30H₂O (469.71): C, 57.28; H, 6.61; N, 8.95. Found: C, 57.34; H.6.67; N, 8.85.

Example 10N-[2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]-N-methylacetamide

Sodium hydride (201.5 mg, 5.04 mmol) was added to a solution ofN-[2-tert-butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]acetamide(549.8 mg, 1.68 mmol) (for preparation see in Example 9) in THF (50 mL)at 0° C. Stirring for 30 min., iodomethane was added. The resultingmixture was stirred overnight at room temperature and quenched withsaturated NaHCO₃ aqueous solution (5 mL) and water (10 mL). Two phaseswere separated. The aqueous was extracted with EtOAc (3×20 mL). Thecombined organic phases were washed with saturated NaHCO₃ aqueoussolution (20 mL), saturated NaCl aqueous solution (20 mL) and dried overNa₂SO₄. After evaporation of the solvent, the residue was purified byMPLC (EtOAc as eluent on silica gel) to give the desired title compoundas a white solid (580.5 mg, 100%). ¹H NMR (400 MHz, CD₃OD): δ 1.26 (m,5H), 1.67 (m, 2H), 1.69 (s, 9H), 1.71 (m, 1H), 1.78 (m, 2H), 1.87 (s,3H), 2.14 (m, 1H), 3.30 (s, 3H), 4.49 (d, J=7.62 Hz, 2H), 7.55 (d,J=8.40 Hz, 1H), 7.71 (s, 1H), 8.00 (d, J=8.40 Hz, 1H). MS (ESI) (M+H)⁺:342.3. Anal. Calcd for C₂₁H₃₁N₃O+1.30 TFA+0.80H₂O (504.14): C, 56.23; H,6.78; N, 8.33. Found: C, 56.21; H, 6.77; N, 8.17.

Example 11N-[2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]-2,2-dimethylpropanamide

Step A:N-[2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]-2,2-dimethylpropanamide

N-{3-Amino-4[(cyclohexylmethyl)amino]phenyl}-2,2-dimethylpropanamide(for preparation, see following Steps B to D) (174 mg, 0.573 mmol) andDMAP (18 mg, 0.143 mmol) were dissolved in 5 mL of DCM. Trimethylacetylchloride (0.077 mL, 0.630 mmol) was added dropwise and the solution wasstirred at RT for 1 h. The solvent was evaporated. The residue wasdissolved in 3 mL of glacial acetic acid in a sealed tube and thesolution was heated at 150° C. in a Smithsynthesizer (PersonalChemistry) microwave instrument for 1 h. The solvent was evaporated invacuo. The residue was dissolved in EtOAc and washed with saturatedNaHCO₃ solution, brine and dried over anhydrous MgSO₄. The product waspurified by reversed-phase HPLC using 20-80% CH₃CN/H₂O on a C-18 columnand then lyophilized affording the desired title compound as thecorresponding TFA salt. Yield: 170 mg (61%). ¹H NMR (400 MHz,METHANOL-D₄): δ 1.21 (m, 5H), 1.29 (s, 9H), 1.61 (m, 2H), 1.64 (s, 9H),1.66 (m, 1H), 1.75 (m, 2H), 2.09 (m, 1H), 4.42 (d, J=7.62 Hz, 2H), 7.62(dd, J=9.18, 1.95 Hz, 1H), 7.81 (d, J=9.18 Hz, 1H), 8.31 (d, J=1.56 Hz,1H); MS (ESI) (M+H)⁺ 370.2; Anal. Calcd for C₂₃H₃₅N₃O+1.6 TFA+0.2H₂O: C,56.64; H, 6.71; N, 7.56. Found: C, 56.67; H, 6.74; N, 7.53.

Step B: N-(4-Fluoro-3-nitrophenyl)-2,2-dimethylpropanamide

4-Fluoro-3-nitroaniline (500 mg, 3.20 mmol) and DMAP (586 mg, 4.80 mmol)were dissolved in 25 mL of DCM. Trimethylacetyl chloride (0.587 mL, 4.80mmol) was added dropwise and the solution was stirred at rt for 3 h. Thesolution was washed with 5% KHSO₄ solution, saturated NaHCO₃ solution,brine and dried over anhydrous MgSO₄. The crude product was purified byflash chromatography using 35% EtOAc in hexanes as eluent on silica gelto produce the desired title compound. Yield: 713 mg (93%). ¹H NMR (400MHz, CHLOROFORM-D:) δ 1.34 (s, 9H), 7.25 (dd, J=10.25, 9.08 Hz, 1H),7.50 (br.s, 1H), 7.88 (ddd, J=9.08, 3.71, 2.83 Hz, 1H), 8.26 (dd,J=6.44, 2.73 Hz, 1H).

Step C:N-{4-[(Cyclohexylmethyl)amino]-3-nitrophenyl}-2,2-dimethylpropanamide

N-(4-Fluoro-3-nitrophenyl)-2,2-dimethylpropanamide (158 mg, 0.658 mmol)and cyclohexylmethylamine (0.100 mL, 0.790 mmol) were stirred in 3 mL ofEtOH containing triethylamine (0.140 mL, 0.987 mmol) at 75° C. for 24 h.The solvent was evaporated. The residue was dissolved in EtOAc andwashed with 5% KHSO₄ solution, saturated NaHCO₃ solution, brine anddried over anhydrous MgSO₄. Yield: 217 mg (99%). ¹H NMR (400 MHz,CHLOROFORM-D): δ 0.98-1.09 (m, 2H), 1.17-1.28 (m, 3H), 1.31 (s, 9H),1.65-1.73 (m, 2H), 1.74-1.80 (m, 2H), 1.82-1.84 (m, 1H), 1.85-1.88 (m,1H), 3.15 (dd, J=6.64, 5.47 Hz, 2H), 6.83 (d, J=9.37 Hz, 1H), 7.23(br.s, 1H), 7.82 (dd, J=9.18, 2.54 Hz, 1H), 8.10 (d, J=2.54 Hz, 1H),8.11-8.13 (m, 1H).

Step D:N-{3-Amino-4[(cyclohexylmethyl)amino]phenyl}-2,2-dimethylpropanamide

N-{4-[(Cyclohexylmethyl)amino]-3-nitrophenyl}-2,2-dimethylpropanamide(215 mg, 0.645 mmol) was dissolved in 20 mL of EtOAc containing acatalytic amount of 10% Pd/C. The solution was shaken in a Parrhydrogenation apparatus under H₂ atmosphere (45 psi) at RT for 24 h. Thesolution was filtered through Celite and the solvent evaporated to givethe desired product. Yield: 175 mg (89%); MS (ESI) (M+H)+304.04.

1. A compound of formula I or a pharmaceutically acceptable saltthereof:

wherein Z is selected from O═ and S═; R¹ is selected fromR⁵R⁶N—C₁₋₆alkyl, R⁵O—C₁₋₆ alkyl, R⁵C(═O)N(—R⁶)—C₁₋₆alkyl,R⁵R⁶NS(═O)₂—C₁₋₆alkyl, R⁵CS(═O)₂N(—R⁶)—C₁₋₆ alkyl,R⁵R⁶NC(═O)N(—R⁷)—C₁₋₆alkyl, R⁵R⁶NS(═O)₂N(R⁷)—C₁₋₆alkyl, C₆₋₁₀aryl-C₁₋₆alkyl, C₆₋₁₀aryl-C(═O)—C₁₋₆alkyl, C₃₋₁₀-cycloalkyl-C₁₋₆alkyl,C₄₋₈cycloalkenyl-C₁₋₆alkyl, C₃₋₆ heterocyclyl-C₁₋₆alkyl,C₃₋₆heterocyclyl-C(═O)—C₁₋₆alkyl, C₁₋₁₀hydrocarbylamino, R⁵R⁶N—, R⁵O—,R⁵C(═O)N(—R⁶)—, R⁵R⁶NS(═O)₂—, R⁵CS(═O)₂N(—R⁶)—, R⁵R⁶NC(═O)N( —R⁷)—,R⁵R⁶NS(═O)₂N(R⁷)—, C₆₋₁₀-aryl, C₆₋₁₀aryl-C(═O)—, C₃₋₁₀cycloalkyl,C₄₋₈cycloalkenyl, C₃₋₆heterocyclyl and C₃₋₆heterocyclyl-C(═O)—; whereinsaid C₆₋₁₀aryl-C₁₋₆alkyl, C₆₋₁₀aryl-C(═O)—C₁₋₆alkyl,C₃₋₁₀cycloalkyl-C₁₋₆alkyl, C₄₋₈cycloalkenyl-C₁₋₆alkyl,C₃₋₆heterocyclyl-C₁₋₆alkyl, C₃₋₆heterocyclyl-C(═O)—C₁₋₆alkyl,C₁₋₁₀hydrocarbylamino, C₆₋₁₀aryl, C₆₋₁₀aryl-C(═O)—, C₃₋₁₀cycloalkyl,C₄₋₈cycloalkenyl, C₃₋₆heterocyclyl or C₃₋₆heterocyclyl-C(═O)— used indefining R¹ is optionally substituted by one or more groups selectedfrom halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and—NR⁵R⁶; R² is selected from the group consisting of C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₆alkyl,C₄₋₈cycloalkenyl-C₁₋₆alkyl, C₃₋₆heterocycloalkyl-C₁₋₆alkyl,C₄₋₈cycloalkenyl, R⁵R⁶N—, C₃₋₅heteroaryl, C₆₋₁₀aryl andC₃₋₆heterocycloalkyl, wherein said C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₆alkyl,C₄₋₈cycloalkenyl-C₁₋₆alkyl, C₃₋₆heterocycloalkyl-C₁₋₆alkyl, C₄₋₈cycloalkenyl, C₃₋₅heteroaryl, C₆₋₁₀aryl or C₃₋₆heterocycloalkyl used indefining R² is optionally substituted by one or more groups selectedfrom halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and—NR⁵R⁶; wherein R⁵, R⁶ and R⁷ are independently selected from —H,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, and a divalent C₁₋₆group thattogether with another divalent R⁵, R⁶ or R⁷ forms a portion of a ring;R³ is selected from R⁸, and R⁸O—; R⁸ is selected from C₃₋₆heterocyclyland C₃₋₆heterocyclyl-C₁₋₆alkyl, wherein said C₃₋₆heterocyclyl orC₃₋₆heterocycly-C₁₋₆alkyl is optionally substituted by one or moregrouns selected from halogen, cyano, nitro, methoxy, ethoxy, methyl,ethyl, hydroxy and amino; and R⁴ is selected from —H, C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₆alkyl,C₃₋₆heterocyclyl, C₆₋₁₀aryl, C₃₋₆heterocylcyl-C₁₋₆alkyl, andC₆₋₁₀aryl-C₁₋₆alkyl, wherein said C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl -C₁₋₆alkyl,C₃₋₆heterocyclyl, C₆₋₁₀aryl, C₃₋₆heterocylcyl-C₁₋₆alkyl,C₆₋₁₀aryl-C₁₋₆alkyl, or divalent C₁₋₆group is optionally substituted byone or more groups selected from halogen, cyano, nitro, methoxy, ethoxy,methyl, ethyl, hydroxy and amino.
 2. A compound as claimed in claim 1,wherein Z is O═; R¹ is selected from R⁵R⁶N—C₁₋₄alkyl, R⁵O—C₁₋₄alkyl,R⁵C(═O)N(—R⁶)—C₁₋₄alkyl, phenyl-C₁₋₄alkyl, phenyl-C(═O)—C₁₋₄alkyl,C₃₋₁₀cycloalkyl-C₁₋₄alkyl, C₄₋₆cycloalkenyl-C₁₋₄alkyl,C₃₋₆heterocyclyl-C₁₋₄alkyl, C₃₋₆heterocyclyl-C(═O)—C₁₋₄alkyl, R⁵R⁶N—,R⁵O—, R⁵R⁶NS(═O)₂—, C₆₋₁₀aryl, C₆₋₁₀aryl -C(═O)—, C₃₋₀₁-cycloalkyl,C₄₋₆cycloalkenyl, C₃₋₆heterocyclyl and C₃₋₆heterocyclyl-C(═O)—; whereinsaid phenyl-C₁₋₄alkyl, phenyl-C(═O)—C₁₋₄ alkyl,C₃₋₁₀cycloalkyl-C₁₋₄alkyl, C₄₋₆cycloalkenyl-C₁₋₄alkyl,C₃₋₆heterocyclyl-C₁₋₄alkyl, C₃₋₆heterocyclyl-C(═O)—C₁₋₄alkyl, C₆₋₁₀aryl,C₆₋₁₀aryl-C(═O)—, C₃₋₁₀cycloalkyl, C₄₋₆ cycloalkenyl, C₃₋₆heterocyclylor C₃₋₆heterocyclyl-C(═O)— used in defining R¹ is optionally substitutedby one or more groups selected from halogen, cyano, nitro, methoxy,ethoxy, methyl, ethyl, hydroxy, and —NR⁵R⁶; wherein R⁵ and R⁶ areindependently selected from —H, C₁₋₆alkyl and C₂₋₆alkenyl; R² isselected from the group consisting of C₁₋₆alkyl, C₂₋₆alkenyl,C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₄alkyl, C₄₋₆cycloalkenyl-C₁₋₄alkyl,C₃₋₆heterocycloalkyl -C₁₋₄alkyl, C₄₋₆cycloalkenyl, C₃₋₅heteroaryl,R⁵R⁶N—, phenyl and C₃₋₆heterocycloalkyl, wherein said C₁₋₆alkyl,C₂₋₆alkenyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₄alkyl,C₄₋₆cycloalkenyl-C₁₋₄alkyl, C₃₋₆heterocycloalkyl-C₁₋₄alkyl,C₄₋₆cycloalkenyl, C₃₋₅heteroaryl, phenyl or C₃₋₆heterocycloalkyl used indefining R² is optionally substituted by one or more groups selectedfrom halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy andamino; and R³ is selected from R⁸, and R⁸O; R⁸ is selected fromC₃₋₆heterocyclyl, and C₃₋₆heterocylcyl-C₁₋₄alkyl wherein saidC₃₋₆heterocyclyl, or C₃₋₆heterocylcyl-C₁₋₄alkyl is optionallysubstituted by one or more groups selected from halogen, cyano, nitro,methoxy, ethoxy, methyl, ethyl, hydroxy and amino; and R⁴ is selectedfrom —H, C₁₋₆alkyl and C₂₋₆alkenyl.
 3. A compound as claimed claim 1,wherein Z is O═; R¹ is selected from R⁵R⁶N—C₁₋₄alkyl, R⁵O—C₁₋₄alkyl,R⁵C(═O)N(—R⁶)—C₁₋₄alkyl, phenyl-C₁₋₄alkyl, phenyl-C(═O)—C₁₋₄alkyl,C₃₋₆cycloalkyl-C₁₋₄alkyl, C₄₋₆cycloalkenyl-C₁₋₄alkyl,C₃₋₆heterocyclyl-C₁₋₄alkyl, C₃₋₆heterocyclyl-C(═O)—C₁₋₄alkyl, phenyl,C₃₋₆cycloalkyl, C₃₋₆heterocyclyl and C₃₋₆heterocyclyl-C(═O)—; whereinsaid R⁵R⁶N—C₁₋₄alkyl, R⁵O—C₁₋₄alkyl, R⁵C(═O)N(—R⁶)—C₁₋₄alkyl,phenyl-C₁₋₄alkyl, phenyl-C(═O)—C₁₋₄alkyl, C₃₋₆cycloalkyl-C₁₋₄alkyl,C₄₋₆cycloalkenyl-C ₁₋₄alkyl, C₃₋₆heterocyclyl-C₁₋₄alkyl,C₃₋₆heterocyclyl-C(═O)—C₁₋₄alkyl, phenyl, C₃₋₆cycloalkyl,C₃₋₆heterocyclyl or C₃₋₆heterocyclyl-C(═O)-used in defining R¹ isoptionally substituted by one or more groups selected from halogen,cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and —NR⁵R⁶; R² isselected from the group consisting of C₁₋₆alkyl, C₃₋₆cycloalkyl, R⁵R⁶N—,C₃₋₆cycloalkyl-C₁₋₄alkyl, C₃₋₆heterocycloalkyl-C₁₋₄alkyl,C₃₋₆heterocycloalkyl, C₃₋₅heteroaryl, and phenyl wherein said C₁₋₆alkyl,C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C ₁₋₄alkyl,C₃₋₆heterocycloalkyl-C₁₋₄alkyl, C₃₋₆heterocycloalkyl, C₃₋₅heteroaryl,and phenyl used in defining R² is optionally substituted by one or moregroups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl,ethyl, hydroxy, and —NR⁵R⁶; R⁵ and R⁶ are independently selected from—H, C₁₋₆alkyl and C₂₋₆alkenyl; and R³ is selected from R⁸ and R⁸O; R⁸ isselected from C₃₋₅heterocyclyl and C₃₋₅heterocylcyl -C₁₋₄alkyl, whereinsaid C₃₋₅heterocyclyl or C₃₋₅heterocylcyl-C₁₋₄alkyl is optionallysubstituted by one or more groups selected from halogen, cyano, methoxy,methyl, and ethyl; and R⁴ is selected from —H and C₁₋₄alkyl.
 4. Acompound as claimed in claim 1, wherein Z is O═; R¹ is selected fromcyclohexylmethyl, cyclopentylmethyl, cyclobutylmethyl,cyclopropylmethyl, adamantyl, adamantylmethyl, benzyl,tetrahydropyranylmethyl, tetrahydrofuranylmethyl,cyclohexyloxy,cyclohexylamino, dimethylaminoethyl, 4-pyridylmethyl, 2-pyridylmethyl,1-pyrrolylethyl, 1-morpholinoethyl, 4,4-difluorocyclohexylmethyl,cyclohexylmethyl, 2-pyrrolidylmehtyl, N-methyl-2-pyrrolidylmethyl,2-piperidylmethyl, N-methyl-2-piperidylmethyl, 3-thienylmethyl,(2-nitrothiophene-5-yl)-methyl, (1-methyl-1H -imidazole-2-yl)methyl,(5-(acetoxymethyl)-2-furyl)methyl), (2,3-dihydro-1H-isoindole-1-yl)methyl, and 5-(2-methylthiazolyl); R² is selected from t-butyl,n-butyl, 2-methyl-2-butyl, cyclohexyl, cyclohexylmethyl, n-pentyl,isopentyl, trifluoromethyl, 1,1-difluoroethyl, N-piperidyl,dimethylamino, phenyl, pyridyl, tetrahydrofuranyl, tetrahydropyranyl,2-methoxy-2-propyl and N-morpholinyl; R³ is selected from pyridyl,imidazolyl, and 2-thienyl; and R⁴ is selected from —H, methyl and ethyl.5. A pharmaceutical composition comprising a compound according to claim1 and a pharmaceutically acceptable carrier.
 6. A pharmaceuticalcomposition comprising a compound according to claim 2 and apharmaceutically acceptable carrier.
 7. A pharmaceutical compositioncomprising a compound according to claim 3 and a pharmaceuticallyacceptable carrier.
 8. A pharmaceutical composition comprising acompound according to claim 4 and a pharmaceutically acceptable carrier.